Gender differences in age-related decline in glomerular filtration rates in healthy people and chronic kidney disease patients

Men with chronic kidney disease (CKD) progress to end-stage CKD at a faster rate than women[1, 2]. This gender-specific difference cannot be fully explained on the basis of differences in blood pressure, glucose metabolism, or serum cholesterol levels. It is speculated that this difference may be related to gender-specific differences in glomerular structure, hemodynamic condition, activity of local cytokines and hormones, gene expression, and/or the effects of sex hormones on kidney cells[3, 4]. However, these differences also exist in healthy genders[5, 6] and cause gender difference in age-related loss of glomerular filtration rate (GFR) in healthy population[7‐9]. Thus, an accurate assessment of the gender-specific CKD progression rate should be based on the gender differences in age-related decline in GFR in healthy individuals. In addition, some previous studies did not observe a faster progression of CKD in men[10, 11]. The gender-specific difference in CKD progression rates reflect not only biological differences but also differences in environmental, socioeconomic, lifestyle, and health care factors, which are not usually considered as risk factors for CKD and its progression[12, 13]. Therefore, to determine the effect of gender alone on CKD progression, these factors should be adjusted. Therefore, we used a randomly sampled population from a well organized CKD screening study to determine gender-specific difference in CKD progression rates after adjusting for the normal age-related GFR decline and after controlling for potential confounding variables, such as health status, socioeconomic status, and lifestyle behaviors.

The healthy, at-risk, and CKD groups consisted of 4569, 7434, and 1573 people, respectively. There were 1396 individuals (10.04%) with microalbuminuria, 104 (0.75%) with proteinuria, and 261 (1.88%) with eGFR < 60 mL·min^-1·1.73 m^-2. In the healthy group, men had higher BMIs, blood pressures, fasting glucose levels, serum lipid levels, and lower education levels than women of similar ages. In the at-risk group, men were younger, had higher diastolic blood pressures, TG levels, and education levels but lower levels of LDL, TC, and HDL than women. In the CKD group, men had higher blood pressures, TG levels, and education levels but lower HDL levels than women. In each health status group, men were more likely to be smokers. Compared to individuals in the healthy group, those in the at-risk and CKD groups were older and fatter and had higher blood pressures and serum lipid levels. For men, the prevalence of smoking was similar in all health status groups and the CKD group had significantly lower education levels than the healthy or at-risk groups. For women, the at-risk and CKD groups had significantly lower education levels and more smokers than the healthy group (Table 1).

The gender differences of adjusted eGFRs in each health status and age groups are shown in Table 2. In the healthy group, men younger than 60 years old had significantly lower eGFRs than women of similar ages. After age 60, this relationship reversed but the difference was not significant. In the at-risk group, men younger than 70 years old had significantly lower eGFRs than women of similar ages. However, in the CKD group, both men and women had similar eGFRs in each age group.

As shown in Table 3, the unadjusted rates of decline of eGFR were 0.51 mL·min^-1·1.73 m^-2·yr^-1 for men and 0.75 mL·min^-1·1.73 m^-2·yr^-1 for women in the healthy group (p < 0.05), 0.53 mL·min^-1·1.73 m^-2·yr^-1 for men and 0.67 mL·min^-1·1.73 m^-2·yr^-1 for women in the at-risk group (p < 0.05), and 0.89 mL·min^-1·1.73 m^-2·yr^-1 for men and 0.88 mL·min^-1·1.73 m^-2·yr^-1 for women in the CKD group (p > 0.05). After adjusting for covariates, the rates of decline of eGFR were 0.51 mL·min^-1·1.73 m^-2·yr^-1 for men and 0.74 mL·min^-1·1.73 m^-2·yr^-1 for women in the healthy group (p < 0.05), 0.60 mL·min^-1·1.73 m^-2·yr^-1 for men and 0.73 mL·min^-1·1.73 m^-2·yr^-1 for women in the at-risk group (p < 0.05), and 0.96 mL·min^-1·1.73 m^-2·yr^-1 for men and 0.91 mL·min^-1·1.73 m^-2·yr^-1 for women in the CKD group (p > 0.05). In addition, we calculated the variation in the rates of decline of eGFR before and after the age of 50. However, there was no significant difference for either gender in each health status group.

Table 3 also shows that the adjusted rates of decline of eGFR (referenced to the healthy group) was 0.10 mL·min^-1·1.73 m^-2·yr^-1 (p < 0.05) for men and -0.03 mL·min^-1·1.73 m^-2·yr^-1 (p > 0.05) for women in the at-risk group and 0.44 mL·min^-1·1.73 m^-2·yr^-1 (p < 0.05) for men and 0.15 mL·min^-1·1.73 m^-2·yr^-1 (p < 0.05) for women in the CKD group. The gender difference of the adjusted rate of decline of eGFR (referenced to the healthy group) was statistically significant for the CKD group (0.29 mL·min^-1·1.73 m^-2·yr^-1, p < 0.05) but not the at-risk group (0.10 mL·min^-1·1.73 m^-2·yr^-1, p > 0.05).

When we used proteinuria to define CKD, we obtained different results for the CKD group (Table 4). For men, the difference of the adjusted rate of decline of eGFR between the CKD and healthy groups increased from 0.44 mL·min^-1·1.73 m^-2·yr^-1 (p < 0.05) (Table 3) to 0.51 mL·min^-1·1.73 m^-2·yr^-1 (p < 0.05) (Table 4). For women, this difference increased from 0.15 mL·min^-1·1.73 m^-2·yr^-1 (p < 0.05) (Table 3) to 0.20 mL·min^-1·1.73 m^-2·yr^-1 (p < 0.05) (Table 4). However, the gender difference of the adjusted rate of decline of eGFR in the CKD group did not show any significant change (0.29 mL·min^-1·1.73 m^-2·yr^-1 vs. 0.31 mL·min^-1·1.73 m^-2·yr^-1). Moreover, these changes were quantitative but not qualitative, which was partly due to the significantly smaller sample size in the CKD group when proteinuria was used to define CKD.

Currently information about gender differences in GFRs in healthy individuals is limited and conflicting. For example, our observation that men younger than 60 years old had lower eGFRs than women of similar ages is both consistent[17] and inconsistent[7, 18‐21] with previous studies. In addition, the information about gender differences in age-related rates of decline of GFR is not very consistent. For instance, our observation that healthy men had lower rates of decline of eGFR than healthy women is in agreement with some previous studies[8, 22] but not others[7, 21, 23]. Unlike the participants in previous studies, who were voluntary kidney donors[7, 8, 18, 20, 21, 23] or local residents[17, 19], participants in this study were selected from a prior stratified cluster sampling study, which represented the study population well and minimized selection bias.

Some earlier studies showed an increase in the rates of decline of GFR in healthy individuals older than 40 or 50 years old[18, 19, 21] or a constant GFR for women younger than 50 years old[23]. However, other studies observed a linear relationship between GFR and age[8, 20]. In this study, we did not find any significant difference in the rate of decline of eGFR before or after the age of 50 for either gender. In addition, although we observed that older healthy subjects had significantly lower eGFRs than young healthy subjects, the difference was not as large as we expected. This finding is consistent with the hypothesis that kidney function may not decrease with age but rather with age-related increases in the incidence of degenerative diseases and risk factors for vascular and kidney disease. In most former studies, few study participants were elderly and exclusion criteria were more relaxed than in our study. Any study about the rate of decline of GFR in healthy individuals that does not exclude all possible confounding factors that can affect the GFR, which are common in the elderly, would be expected to show an increased rate of decline of GFR in the elderly.

Our observation that the rate of decline of eGFR in men was slower in the healthy group but faster in the CKD group could be explained by epidemiology studies. In general, men have a higher incidence and prevalence of end-stage renal disease (ESRD) than women [24, 25]; however, most population-based CKD screening studies show that men have a similar[14, 26] or lower[27‐29] prevalence of CKD than women. This discrepancy suggests 2 potential mechanisms for the rate of decline of GFR between non-CKD and CKD stages. One possible explanation is that renal function is preserved as healthy individuals age at the expense of a gradual decrease in the renal functional reserve[30]. Men may have a higher renal functional reserve to compensate for the accumulation of sclerotic glomeruli during aging. Indeed, previous studies show that healthy men have a greater ability to maintain their GFRs by increasing the filtration fraction than women[31]. In addition, gender-specific differences in glomerular hemodynamic may contribute to differences in age-related decline of GFRs. Another possible explanation is that although the whole-body levels[6] and renal levels[32] of nitric oxide, a vasodilator, are higher in healthy premenstrual women than healthy men, which may cause a higher GFR in premenstrual women, the renal vasculature of men may become increasingly dependent on nitric oxide with age compared with that of women[5]. If this is true, then any renal disease that interferes with nitric oxide production may cause kidney damage to progress more quickly in men than in women.

This study had 3 potential limitations. First, the use of estimated GFR to assess renal function in healthy individuals could be prone to measurement bias[17]. However, when we used the Cockcroft-Gault formula, which was developed from healthy individuals and is more accurate than the MDRD formula[17], to assess renal function in healthy individuals, men still had lower eGFRs and slower age-related rates of decline of eGFR than women. Furthermore, when we excluded individuals younger than 30 years old (who are healthier), our results were similar. Second, we had to estimate GFRs rather than measure them directly and only a single measurement of serum creatinine was available for each participant. In addition, morning spot urine samples were collected rather than first morning void urine samples. It is known that first morning void urine samples may provide more accurate results of albuminuria [33] and that the reproducibility of microalbuminuria tests is limited (60-70%) [34]. Despite these limitations, the procedures used in this study were chosen due to the expense and inherent difficulties of directly measuring GFRs and collecting first-morning void urine samples and many blood and urine samples in a study with more than 10,000 participants. Third, estimating age-related rates of decline of eGFR from a cross-sectional study undoubtedly produced bias; however, appropriate mathematical models were used to reduce the bias as much as possible. In addition, since men had a higher risk of cardiovascular disease and death with increasing age, especially those with chronic renal insufficiency, the regression line of GFR against age would deviate from its actual trend for a higher non-response rate in men than in women. However, in this study, men had a similar response rate as that in women (89.6% vs. 92.1%). Moreover, if a correction were made for the higher non-response rate in unhealthy men, who tended to have lower GFRs than participants who responded, then the gender differences in the rate of decline of eGFR would be greater.

There are gender differences in the decline in GFR and among different health statuses. To accurately evaluate the gender differences in CKD progression rate, the baseline gender differences in age-related decline in GFR in healthy individuals should be considered.